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摘要 : David Stuart 及同事发表了埃博拉病毒糖蛋白的第一个无配体结构。

 David Stuart 及同事发表了埃博拉病毒糖蛋白的第一个无配体结构。该糖蛋白是负责宿主细胞附着和膜融合的惟一病毒蛋白,因此从逻辑上来说也是抗病毒药物研发的一个目标。他们还确定了该糖蛋白在与两种以前被发现对埃博拉病毒复制有抑制作用的药物(这两种药物分别是toremifene 和ibuprofen)所形成的复合物中的结构,从而有助于了解这些药物是怎样抑制病毒与核内体膜(endosomal membrane)融合的。


Toremifene interacts with and destabilizes the Ebola virus glycoprotein


Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion1, 2, 3, 4, 5, 6, 7. GP is thus a primary target for the development of antiviral drugs. Here we report the first, to our knowledge, unliganded structure of EBOV GP, and high-resolution complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resolution apo structure gives a more complete and accurate picture of the molecule, and allows conformational changes introduced by antibody and receptor binding to be deciphered8, 9, 10. Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equivalent tunnels from the other monomers of the trimer at the three-fold axis. Protein–drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14 °C decrease in the protein melting temperature after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs.

来源: Nature 浏览次数:0


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